PROJECT SUMMARY: This project aims to investigate the molecular mechanisms of olaparib resistance in metastatic castration- resistant prostate cancer (mCRPC). Cancers harboring specific deficiencies in the DNA damage response pathway are exceptionally sensitive to poly(ADP-ribose) polymerase inhibition (PARPi), especially tumors harboring bi-allelic loss of the breast cancer genes (BRCA1 and BRCA2). PARPi are clinically approved in breast and ovarian cancer, but drug resistance remains a problem. Recent work has shown that genetic alteration of BRCA2 is frequent in mCRPC, and confers sensitivity to the clinically important PAPRi olaparib, which has achieved breakthrough designation in mCRPC; however, resistance is anticipated. The long-term success of PARPi in the clinic for mCRPC depends on a complete understanding the molecular mechanisms of resistance that may arise. Although the mechanisms of resistance to PARPi have been extensively studied in breast and ovarian cancer, mCRPC is likely to present unique mechanisms of resistance for multiple reasons. Firstly, genetic alteration of BRCA2 in prostate cancer occurs primarily through deletion; whereas in breast and ovarian cancer, mutation is more frequent. This difference affects the types of resistance mechanisms that can be observed, shifting to BRCA2-independent mechanisms. Secondly, the genetic landscape of mCRPC differs from ovarian and breast cancer. Lastly, the administration of standard of care therapies such as second-generation antiandrogens in mCRPC has the potential to alter the response to PARPi. For these reasons, investigation of resistance mechanisms in biologically relevant and genetically controlled prostate cancer model systems will be necessary for the success of PARPi in mCRPC. Here, we propose to use human and murine BRCA2-deleted prostate organoid, cell line, and patient derived xenograft (PDX) models to identify gene drivers and molecular mechanisms of olaparib resistance. In addition to performing research on an important clinical question in mCRPC, this fellowship proposal represents an excellent opportunity for training and career development. My long-term career goal is to perform independent academic research, and completing the proposed work under the supervision of Dr. Charles Sawyers at MSKCC provides the ideal training environment to achieve this goal. During my postdoctoral fellowship, I will not only improve my technical and laboratory skill set, but I will also focus on improving my scientific communication skills in teaching, presentations, writing, and grantsmanship, which are necessary components for a successful career in academic research.